Ultimately, the true test of the cascade hypothesis is to conduct

Ultimately, the true test of the cascade hypothesis is to conduct a true primary prevention trial with anti-Aβ therapy in patients destined to develop AD but prior to the onset of measureable Aβ deposition. Alternatively, one might envision that the hypothesis could be reasonably well tested in secondary prevention (very early intervention) trial in subjects with Aβ pathology only, prior to the neurodegenerative phase (preclinical

stage 1). In the later scenario, the test potentially would be more effective if the therapeutic modality enhanced clearance of Aβ. In order to conduct a primary prevention study with a therapeutic agent selleckchem for any disease, one needs a strong scientific rationale. Although the Aβ aggregate/amyloid hypothesis is not without its critics, it has very strong scientific underpinnings. In the context of trying to move the field toward primary prevention studies with anti-Aβ therapies, it is important to consider the views of those who are skeptical about the role of Aβ in AD.

One valid critique of the hypothesis is that most of the experimental evidence supporting the hypothesis comes from the study of the genetic alterations that cause familial autosomal dominant AD (Selkoe, 2001 and Younkin, 1998). Thus, a key assumption check details is that pathological cascades in sporadic AD are the same as in familial AD. Given that the typical genetic and sporadic forms of AD are very similar with respect to postmortem findings, clinical course, and evidence from the emerging biomarker and imaging cascade in sporadic AD, this seems a reasonable assumption (

Shepherd et al., 2009). Indeed, when examples from other human diseases with genetic and sporadic forms, such as hypercholesterolemia and prion diseases, are considered, this concept is quite tenable ( Brown and Goldstein, 1986 and Prusiner, 1998). Nevertheless, Florfenicol because of the late age of onset, sporadic AD is not a completely uniform clinical or pathological entity: it is complicated by other systemic or CNS illnesses and conditions, and the biological processes of aging. Thus, the underlying brain pathology that results in clinical dementia may represent the convergence of independent processes and not necessarily a single pathologic entity ( Small and Duff, 2008), as thought to be the case in early onset familial AD. Indeed, in the over-80-year-old population who have died with a clinical diagnosis of probable AD dementia, postmortem phenotypes often show not only plaques and tangles pathology characteristic of AD, but other proteinopathies and vascular insults as well ( Dickson, 2001). However, even if this is the case, and multiple pathologies synergize in some subpopulations of those affected with what we define as AD, one might still predict that preventing Aβ deposition would have substantial, but perhaps not complete, efficacy.

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